Azolopyridin-2-one derivatives as lipase and phospholipase inhibitors

ABSTRACT

The present invention provides compounds which have an inhibitory effect on hormone-sensitive lipase or endothelial lipase. The compounds of the invention are azolopyridin-2-one derivatives of the general formula I 
     
       
         
         
             
             
         
       
         
         
           
             wherein the substituents are as defined herein. The compounds of formula I wherein R2 is hydrogen are distinguished by favorable effects on disorders of lipid metabolism. They beneficially influence the HDL to LDL ratio and increase in particular the HDL level and are suitable for the prevention and treatment of dyslipidemias and metabolic syndrome and their diverse sequelae such as atherosclerosis, coronary heart disease, heart failure, obesity and diabetes. The compounds of formula I wherein R1 and R2 together form a ring system are distinguished by favorable effects on metabolic disorders. They beneficially influence lipid and sugar metabolism; in particular they lower the triglyceride level and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and the diverse sequelae thereof.

This application is a continuation of International application No.PCT/EP2006/005,095, filed May 27, 2006, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofGerman Patent Application No. 10 2005 026 762.9, filed Jun. 9, 2005.

The present invention relates to azolopyridin-2-one derivatives of thegeneral formula I, to their pharmaceutically useful salts and to theiruse as medicinal substances.

Compounds of similar structure are known from EP 1275653. However, theseare used as fungicides.

Compounds having an inhibitory effect on hormone-sensitive lipase aredescribed in the prior art for example in WO2004/035550, WO2005/073199or WO03/051842.

Compounds with an inhibitory effect on endothelial lipase are describedin the prior art for example in WO2004/094394, WO2004/094393.

The present invention provides compounds which have an inhibitory effecton hormone-sensitive lipase or endothelial lipase.

The invention relates to azolopyridin-2-one derivatives of the generalformula I

in which the meanings are:

-   X identically or differently ═C(—R)— or ═N—, where at least one and    at most two ═C(—R—)— is replaced by ═N—;-   Y —O— or —S—;-   R identically or differently hydrogen, halogen, (C₁-C₆)-alkyl,    (C₁-C₃)-alkyloxy-(C₁-C₃)-alkylene, hydroxy, (C₁-C₆)-alkylmercapto,    amino, (C₁-C₆)-alkylamino, di-(C₂-C₁₂)-alkylamino,    (C₁-C₆)-alkylcarbonyl, COOR3, trifluoromethyl,    (C₁-C₆)-alkylsulfonyl, (C₁-C₆)-alkylsulfinyl, aminosulfonyl,    pentafluorosulfanyl, (C₆-C₁₀)-aryl, (C₆-C₁₂)-heteroaryl, CO—NR6R7,    O—CO—NR6R7, O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl, O—CO    —(C₁-C₆)-alkylene-CO—OH, O—CO—(C₁-C₆)-alkylene-CO—NR6R7 or    unsubstituted or mono- or poly-F-substituted (C₁-C₆)-alkyloxy;-   R1 is (C₄-C₁₆)-alkyl, (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₄)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₄)-alkylene-(C₃-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where aryl,    heteroaryl, cycloalkyl or bicycle may be substituted one or more    times by halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy, hydroxy,    (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,    di-(C₂-C₁₂)-alkylamino, mono-(C₁-C₆)-alkylaminocarbonyl,    di-(C₂-C₈)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl,    (C₁-C₆)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy,    (C₁-C₆)-alkylsulfonyl, aminosulfonyl;-   R2 is hydrogen, (C₁-C₆)-alkyl; or-   R1 and R2 form together with the nitrogen atom bearing them a    monocyclic, saturated or partially unsaturated 4- to 7-membered ring    system or a bicyclic saturated or partially unsaturated 8- to    14-membered ring system, of which individual members of the ring    systems may be replaced by one to three atoms or atomic groups from    the series —CHR4-, —CR4R5-, —(C═R4)-, —NR6-, —C(═O)—, —O—, —S—,    —SO—, —SO₂—, with the proviso that two units from the series —O—,    —S—, —SO—, —SO₂— may not be adjacent;-   R3 hydrogen, (C₁-C₆)-alkyl, benzyl;-   R4, R5 identically or differently (C₁-C₆)-alkyl, halogen,    trifluoromethyl, COOR3, cyclopropyl, cyclopropylene;-   R6, R7 identically or differently hydrogen, (C₁-C₆)-alkyl,    —(C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl, (C₃-C₁₂)-cycloalkyl,    (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₄)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₄)-alkylene-(C₄-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle;    the tautomeric forms of the compounds and the physiologically    tolerated salts thereof.

Preferred compounds of the formula I are those in which

-   R1 is (C₅-C₁₆)-alkyl, (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₄)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₄)-alkylene-(C₃-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where aryl,    heteroaryl, cycloalkyl or bicycle may be substituted one or more    times by halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy, hydroxy,    (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,    di-(C₂-C₁₂-alkylamino, mono-(C₁-C₆)-alkylaminocarbonyl,    di-(C₂-C₈)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl,    (C₁-C₆)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy,    (C₁-C₆)-alkylsulfonyl, aminosulfonyl.

Particularly preferred compounds of the formula I are those in which

-   X is identically or differently ═C(—R)— or ═N—, where one ═C(—R—)—    is replaced by ═N—;    -   Y is —O—, —S—;-   R is identically or differently hydrogen, halogen, (C₁-C₆)-alkyl,    hydroxy, trifluoromethyl, mono-(C₁-C₆)-alkylaminocarbonyl,    di-(C₂-C₈)-alkylaminocarbonyl, COOR3, (C₁-C₆)-alkylsulfonyl,    aminosulfonyl, (C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl,    (C₁-C₆)-alkylcarbonyl, CO—NR6R7, O—CO—NR6R7,    O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl,    O—CO—(C₁-C₆)-alkylene-CO—NR6R7 or unsubstituted or mono- or    poly-F-substituted (C₁-C₆)-alkyloxy;-   R1 is (C₆-C₁₂)-alkyl, (C₁-C₃)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₃)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₃)-alkylene-(C₄-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where aryl,    heteroaryl, cycloalkyl or bicycle may be substituted one or more    times by halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy, hydroxy, amino,    (C₁-C₆)-alkylamino, trifluoromethyl;-   R2 is hydrogen, (C₁-C₆)-alkyl; or-   R1 and R2 together with the nitrogen atom bearing them are a    monocyclic, saturated 5-to 6-membered ring system or a bicyclic    saturated or partially unsaturated 9-to 10 membered ring system, of    which individual members of the ring systems may be replaced by one    to three atoms or atomic groups from the series —CHR4-, —CR4R5-,    —(C═R4)-, —NR6-, —O—, —S—, with the proviso that two units from the    series —O—, —S— may not be adjacent;-   R3 is hydrogen, (C₁-C₆)-alkyl, benzyl;-   R4, R5 are identically or differently (C₁-C₆)-alkyl, halogen,    trifluoromethyl, COOR3, cyclopropyl, cyclopropylene;-   R6, R7 are identically or differently hydrogen, (C₁-C₆)-alkyl,    (C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl, (C₃-C₁₂)-cycloalkyl,    (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₄)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₄)-alkylene-(C₄-C₁₂)-cycloalkyl, (C₆-C₁₄)-bicycle.

Particularly preferred compounds of the formula I are also those inwhich

-   X is identically or differently ═C(—R)— or ═N—, where at least one    ═C(—R—)— is replaced by ═N;-   Y is —O— or —S—;-   R is identically or differently hydrogen, halogen, (C₁-C₆)-alkyl,    hydroxy, trifluoromethyl, mono-(C₁-C₆)-alkylaminocarbonyl,    di-(C₂-C₈)-aryl, (C₅-C₁₂)-heteroaryl, (C₁-C₆)-alkylcarbonyl,    CO—NR6R7, O—CO—NR6R7, O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl,    O—CO—(C₁-C₆)-alkylene-CO—NR6R7 or unsubstituted or mono- or    poly-F-substituted (C₁-C₆)-alkyloxy;-   R1 is (C₆-C₁₂)-alkyl, (C₁-C₂)-alkylene-(C₆-C₁₀)-aryl,    (C₁-C₂)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₂)-alkylene-(C₄-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where aryl,    heteroaryl, cycloalkyl or bicycle may be substituted one or more    times by halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy, hydroxy, amino,    (C₁-C₆)-alkylamino, trifluoromethyl;    -   R2 is hydrogen; or-   R1 and R2 together with the nitrogen atom bearing them are a    monocyclic, saturated 5-to 6-membered ring system or a bicyclic    saturated or partially unsaturated 9-to 10 membered ring system, of    which individual members of the ring systems may be replaced by one    to three atoms or atomic groups from the series —CHR4-, —CR4R5-,    —(C═R4)-, —NR6-, —O—, —S—, with the proviso that two units from the    series —O—, —S— may not be adjacent;    -   R3 is hydrogen, (C₁-C₆)-alkyl, benzyl;-   R4, R5 are identically or differently (C₁-C₆)-alkyl, halogen,    trifluoromethyl, COOR3, cyclopropyl, cyclopropylene;-   R6, R7 are identically or differently hydrogen, (C₁-C₆)-alkyl,    —(C₆-C₁₀)-aryl, (C₃-C₁₂)-cycloalkyl, (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl.

In a further particularly preferred embodiment of the compounds of theformula I,

-   R6, R7 are identically or differently hydrogen, (C₁-C₆)-alkyl or    (C₃-C₆)-cycloalkyl.

Preferred compounds of the formula I are also those in which

-   X in position 5, 6 and 7 is identically or differently ═C(—R)—, in    position 4 is ═N—.

Further preferred compounds of the formula I are those in which

-   X where appropriate in position 4 or 7 is ═C(—R)— with R=hydrogen,    in position 5 or 6 is ═C(—R)— with R not hydrogen.

Very particularly preferred compounds of the formula I are those inwhich

-   Y is —O—, —S—;-   R1 is (C₆-C₁₂)-alkyl, benzyl, (C₁-C₃)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₃)-alkylene-(C₄-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where    benzyl, heteroaryl, cycloalkyl or bicycle may be substituted by    halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy or trifluoromethyl;-   R2 is hydrogen; or-   R1 and R2 together with the nitrogen atom bearing them form a    monocyclic, saturated 5- to 6-membered ring system, of which    individual members of the ring systems may be replaced by one to two    atoms or atomic groups from the series —CHR4-, —NR6-, in which R4 is    as defined above, and R6 is (C₁-C₆)-alkyl or cyclopropyl.

In one embodiment of the compounds of the formula I,

-   X is identically or differently ═C(—R)— or ═N—, where one ═C(—R—)—    is replaced by ═N—;

In one embodiment of the compounds of the formula I,

-   Y is —O—.

In another embodiment of the compounds of the formula I,

-   Y is —S—.

In a particular embodiment of the compounds of the formula I,

-   R2 is hydrogen.

Further very particularly preferred compounds of the formula I are thosein which

-   Y is —O—;-   R is identically or differently hydrogen, halogen, hydroxy or    (C₁-C₆)-alkyl;-   R1 is (C₇-C₁₂)-alkyl, benzyl, (C₁-C₃)-alkylene-(C₅-C₁₂)-heteroaryl,    (C₁-C₃)-alkylene-(C₄-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where    benzyl, heteroaryl, cycloalkyl or bicycle may be substituted by    halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkoxy or trifluoromethyl;-   R2 is hydrogen.

Further very particularly preferred compounds of the formula I are alsothose in which

-   Y is —O—;-   R is identically or differently hydrogen, halogen or (C₁-C₆)-alkyl;-   R1 is (C₆-C₁₂)-alkyl, benzyl, —CH₂—(C₅-C₁₂)-heteroaryl,    —CH₂—(C₄-C₁₂)-cycloalkyl, (C₈-C₁₄)-bicycle, where benzyl,    heteroaryl, cycloalkyl or bicycle may be substituted by halogen,    (C₁-C₆)-alkyl, (C₁-C₃)-alkoxy or trifluoromethyl;-   R2 is hydrogen.

Further very particularly preferred compounds of the formula I are alsothose in which

-   Y is —O—;-   R is identically or differently hydrogen, halogen or (C₁-C₆)-alkyl;-   R1 is (C₆-C₁₂)-alkyl, benzyl, —CH₂—(C₄-C₁₂)-cyclohexyl, indanyl,    tetrahydronaphthyl, where benzyl, cyclohexyl, indanyl or    tetrahydronaphthyl may be substituted by (C₁-C₆)-alkyl;-   R2 is hydrogen.

The invention relates to compounds of the formula I in the form of theirsalts, racemates, racemic mixtures and pure enantiomers, and to theirdiastereomers and mixtures thereof.

The alkyl and alkylene radicals in the substituents R, R1, R2, R3, R4,R5, R6 and R7 may be either straight-chain or branched. Halogen isfluorine, chlorine, bromine or iodine, in particular fluorine orchlorine. The alkyl and alkylene radicals may be substituted one or moretimes by suitable groups

Aryl means an aromatic carbocyclic mono- or bicyclic ring system whichcomprises 6 to 10 atoms in the ring or in the rings.

The aryl radicals may be substituted one or more times by suitablegroups.

Heteroaryl is a mono- or bicyclic aromatic ring system having 5 to 12ring members, in which at least one atom in the ring system is aheteroatom from the series N, O and S.

Suitable “heteroaryl rings” or “heteroaryl radicals” are, for example,benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, quinolinyl, furyl, furazanyl, imidazolyl,1H-indazolyl, indolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyridyl, pyrrolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiophenyl.

Preferred heteroaryl radicals are thiophenyl, pyrazolyl and pyridyl. Theheteroaryl rings or heteroaryl radicals may be substituted one or moretimes by suitable groups.

A cycloalkyl radical is a ring system which comprises one or more ringsand which is in saturated or partially unsaturated (with one or twodouble bonds) form and which is composed exclusively of carbon atoms.

The cycloalkyl radicals may be substituted one or more times by suitablegroups.

Bicycle means bicyclic ring systems which are in saturated or partiallyunsaturated form and which, apart from carbon, may also comprise one ormore heteroatoms such as, for example, nitrogen, oxygen or sulfur. Thisdefinition also includes ring systems which comprise a fused benzenenucleus. Examples which may be mentioned are the tetrahydronaphthyl,alpha- or beta-tetralon-, indanyl- or indan-1-on-yl radical. Preferredbicyclic radicals are those of formula Ic

with q=1 or 2. The bicyclic radicals may be substituted one or moretimes by suitable groups.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts)and alkaline earth metal salts (such as magnesium and calcium salts) andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the inventionof the formula I, for example an ester, which on administration to amammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of thecompounds of the invention as, for example, described in H. Okada etal., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

Use

The compounds of the invention of the general formula I have asurprising inhibitory effect on hormone sensitive lipase, HSL, anallosteric enzyme in adipocytes which is inhibited by insulin and isresponsible for the breakdown of fats in fat cells and thus fortransferring fat constituents into the blood stream. Inhibition of thisenzyme is therefore equivalent to an insulin-like effect of thecompounds of the invention, eventually leading to a reduction of freefatty acids in the blood and of blood glucose. They can therefore beemployed for metabolic derangements such as, for example, fornon-insulin-dependent diabetes mellitus, for diabetic syndrome and fordirect pancreatic damage.The compounds of the invention of the general formula I, especiallythose in which R2 is hydrogen, may additionally have an inhibitoryeffect on endothelial lipase (EL). The preferred substrate for EL isHDL, which has antiatherosclerotic activity. A reduction in the HDLlevel leads to progression of atherosclerosis and its sequelae such ascoronary heart disease and moreover favors development of the metabolicsyndrome and its sequelae diabetes. An inhibition of EL should thusgenerally lead to prevention of atherosclerotic disorders and indirectlyreduce the probability of people with an increased risk for diabetesbecoming ill.

It has further been found that the inhibitory effect of the compounds ofthe invention of the general formula I is selective in relation to otherlipases.

The compounds of the invention of the formula I may also have aninhibitory effect on triglyceride lipase.

Compounds of this type are particularly suitable for the treatmentand/or prevention of

-   1.—Disorders of fatty acid metabolism and glucose utilization    disorders-   2.—Disorders of the insulin sensitivity of myo-, adipo- and    hepatocytes (insulin resistance)—metabolic syndrome-   3. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.

Particular aspects in this connection are

-   -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,        -   protection of the pancreatic β cells        -   prevention of macro- and microvascular disorders

-   4. Dyslipidemias and the sequelae thereof such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc., especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations        -   low HDL cholesterol concentration        -   low apoA lipoprotein concentrations        -   high LDL cholesterol concentrations        -   small dense LDL cholesterol particles        -   high apoB lipoprotein concentrations

-   5. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   obesity (excess weight), including central obesity    -   thromboses, hypercoagulable and prothrombotic stages (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy

-   6. Other disorders or conditions in which inflammatory reactions or    cell differentiation may for example be involved are:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke    -   vascular restenosis or reocclusion    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis    -   pancreatitis    -   other inflammatory states    -   retinopathy    -   adipose cell tumors    -   adipose cell carcinomas such as, for example, liposarcoma    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and of        the urinary tract, of the genital tract, prostate carcinomas        etc. acute and chronic myeloproliferative disorders and        lymphomas angiogenesis    -   neurodegenerative disorders    -   Alzheimer's disease    -   multiple sclerosis    -   Parkinson's disease erythemato-squamous dermatoses such as, for        example, psoriasis    -   acne vulgaris    -   other skin disorders and dermatological conditions which are        modulated by PPAR    -   eczemas and neurodermatitis dermatitis such as, for example,        seborrheic dermatitis or photodermatitis    -   keratitis and keratosis such as, for example, seborrheic        keratoses, senile keratoses, actinic keratosis, photo-induced        keratoses or keratosis follicularis    -   keloids and keloid prophylaxis    -   warts, including condylomata or condylomata acuminata    -   human papilloma viral (HPV) infections, such as, for example,        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia    -   papular dermatoses such as, for example, lichen planus    -   skin cancer such as, for example, basal cell carcinoma,        melanomas or cutaneous T-cell lymphomas    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi    -   chilblains    -   high blood pressure    -   syndrome X    -   polycystic ovary syndrome (PCOS)    -   asthma    -   osteoarthritis    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   vasculitis    -   wasting (cachexia)    -   gout    -   ischemia/reperfusion syndrome    -   acute respiratory distress syndrome (ARDS)

Formulations

The amount of a compound of the invention necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, from 0.1 ng to 10 mg,typically from 1 ng to 10 mg, per milliliter. Single doses may contain,for example, from 1 mg to 10 g of the active ingredient. Thus, ampoulesfor injections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, tablets or capsules, may contain, for example, from 0.05 to1000 mg, typically from 0.5 to 600 mg. For the therapy of theabovementioned conditions, the compounds of formula I may be used as thecompound itself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of the invention. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units such as, for example, capsules, cachets,suckable tablets or tablets, each of which contain a defined amount ofthe compound of formula I; as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one ormore surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I with R2 hydrogen are distinguished byfavorable effects on disorders of lipid metabolism. They beneficiallyinfluence the HDL to LDL ratio and increase in particular the HDL leveland are suitable for the prevention and treatment of dyslipidemias andmetabolic syndrome and their diverse sequelae such as atherosclerosis,coronary heart disease, heart failure, obesity and diabetes.

The compounds of the formula I with R1 and R2, which form a ring system,are distinguished by favorable effects on metabolic disorders. Theybeneficially influence lipid and sugar metabolism, in particular theylower the triglyceride level and are suitable for the prevention andtreatment of type II diabetes and arteriosclerosis and the diversesequelae thereof.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, favorable effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

-   -   1. medicaments which lower blood glucose, antidiabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. antiatherosclerotic medicaments,    -   4. antiobesity agents,    -   5. antiinflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. antithrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment and/or prevention of        complications caused by diabetes or associated with diabetes.

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Examples which may be mentioned are:

Antidiabetics

Suitable antidiabetics are disclosed for example in the Rote Liste 2001,chapter 12 or in the USP Dictionary of USAN and International DrugNames, US Pharmacopeia, Rockville 2003. Antidiabetics include allinsulins and insulin derivatives such as, for example, Lantus® (seewww.lantus.com) or Apidra, and other fast-acting insulins (see U.S. Pat.No. 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 orelse, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S.

The orally effective hypoglycemic active ingredients include,preferably, the sulfonylureas which act on the ATP-dependent potassiumchannel of the beta cells (e.g. disclosed in WO 97/26265 and WO99/03861), biguanides, meglitinides, glucagon antagonists, oral GLP-1agonists, DPP-IV inhibitors, insulin sensitizers, e.g. PPAR and PXRmodulators and active ingredients such as, for example,oxadiazolidinediones, thiazolidinediones, inhibitors of liver enzymeswhich are involved in stimulating gluconeogenesis and/or glycogenolysis,modulators of glucose uptake such as, for example, glucosidaseinhibitors, compounds which alter lipid metabolism and lead to a changein the blood lipid composition, compounds which reduce food intake orfood uptake.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with substances which influence hepaticglucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188).

In one embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, sulfonylureas(e.g. tolbutamide, glibenclamide, glipizide, glimepiride) or glinides(e.g. repaglinide).

In one embodiment, the compounds of the formula I are administered incombination with a biguanide such as, for example, metformin.

In one embodiment, the compounds of the formula I are administered incombination with a PPARgamma agonist or thiazolidinedione such as, forexample, ciglitazone, pioglitazone, rosiglitazone or the compoundsdisclosed in WO 97/41097 of Dr. Reddy's Research Foundation, inparticular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered incombination with a DPPIV inhibitor as described, for example, inWO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO 02/38541,WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

In one embodiment, the compounds of the formula I are administered incombination with compounds with an inhibitory effect on SGLT-1 and/or 2,as disclosed directly or indirectly for example in WO2004/007517,WO2004/052902, WO2004/052903 and WO2005/121161.

In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid Modulators

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor such aslovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897, U.S. Pat.No. 6,277,831, EP 0683 773, EP 0683 774).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol resorption inhibitor asdescribed for example in WO 0250027, or ezetimibe, tiqueside,pamaqueside.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

In one embodiment, the compounds of the formula I are administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6)). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hoechst, 65926 Frankfurt/Main). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPARalpha agonist.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with nicotinic acid or niacin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, e.g. CP-529, 414(torcetrapib).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor such as, for example,implitapide.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor such as, forexample, orlistat.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide;hydrochloride (CGP 71683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride(SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol;hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),bombesin agonists, galanin antagonists, growth hormone (e.g. humangrowth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tertiary butyl ester (WO 01/85695)), TRH agonists (see, forexample, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO00/78312), RXR modulators or TR-13 agonists.

In another embodiment, the further active ingredient is a cannabinoidreceptor 1 antagonist (such as, for example, rimonabant, SR147778 orthose as are described in, for example, EP 0656354, WO 00/15609, WO02/076949, WO2005080345, WO2005080328, WO2005/080343, WO2005/075450,WO2005/080357, WO2001/70700, WO2003/026647-48, WO2003/02776,WO2003/040107, WO2003/007887, WO2003/027069, U.S. Pat. No. 6,509,367,WO2001/32663, WO2003/086288, WO2003/087037, WO2004/048317,WO2004/058145, WO2003/084930, WO2003/084943, WO2004/058744,WO2004/013120, WO2004/029204, WO2004/035566, WO2004/058249,WO2004/058255, WO2004/058727, WO2004/069838, US2004/0214837,US2004/0214855, US2004/0214856, WO2004/096209, WO2004/096763,WO2004/096794, WO2005/000809, WO2004/099157, US2004/0266845,WO2004/110453, WO2004/108728, WO2004/000817, WO2005/000820,US2005/0009870, WO2005/00974, WO2004/111033-34, WO2004/11038-39,WO2005/016286, WO2005/007111, WO2005/007628, US2005/0054679,WO2005/027837, WO2005/028456, WO2005/063761-62, WO2005/061509,WO2005/077897).

In one embodiment of the invention, the further active ingredient isleptin.

In one embodiment, the further active ingredient is dexamphetamine,amphetamine, mazindole or phentermine.

In one embodiment, the compounds of the formula I are administered incombination with medicaments having effects on the coronary circulationand the vascular system, such as, for example, ACE inhibitors (e.g.ramipril), medicaments which act on the angiotensin-renine system,calcium antagonists, beta blockers etc.

In one embodiment, the compounds of the formula I are administered incombination with medicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I are administered incombination with medicaments which are employed for cancer therapy andcancer prevention.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the presentinvention.

The activity of the compounds of the invention of the formula I wastested in the following enzyme assay systems:

1. HSL Inhibition Assay

1.1. Preparation of the Partially Purified HSL:

Isolated rat fat cells are obtained from epididymal adipose tissue fromuntreated male rats (Wistar, 220-250 g) by collagenase treatment inaccordance with published methods (e.g. S, Nilsson et al., Anal.Biochem. 158, 1986, 399-407; G. Fredrikson et al., J. Biol. Chem. 256,1981, 6311-6320; H. Tornquist et al., J. Biol. Chem. 251, 1976,813-819). The fat cells from 10 rats are washed three times by flotationwith 50 ml of homogenization buffer (25 ml Tris/HCl, pH 7.4, 0.25 Msucrose, 1 mM ETDA, 1 mM DTT, 10 μg/ml leupeptin, 10 μg/ml antipain, 20μg/ml pepstatin) each time and finally taken up in 10 ml ofhomogenization buffer. The fat cells are homogenized in aTeflon-in-glass homogenizer (Braun-Melsungen) by 10 strokes at 1500 rpmand 15° C. The homogenate is centrifuged (Sorvall SM24 tubes, 5000 rpm,10 min, 4° C.). The subnatant between the layer of fat at the top andthe pellet is removed and the centrifugation is repeated. The subnatantresulting therefrom is centrifuged again (Sorvall SM24 tubes, 20 000rpm, 45 min, 4° C.). The subnatant is removed, and 1 g ofheparin-Sepharose (Pharmacia-Biotech, CL-6B, washed 5× with 25 mMTris/HCl, pH 7.4, 150 mM NaCl) is added. After incubation at 4° C. for60 min (shaking at intervals of 15 min), the mixture is centrifuged(Sorvall SM24 tubes, 3000 rpm, 10 min, 4° C.). The supernatant isadjusted to pH 5.2 by adding glacial acetic acid and is incubated at 4°C. for 30 min. The precipitates are collected by centrifugation (SorvallSS34, 12 000 rpm, 10 min, 4° C.) and suspended in 2.5 ml of 20 mMTris/HCl, pH 7.0, 1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10 μg/mlleupeptin/pepstatin/antipain. The suspension is dialyzed against 25 mMTris/HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 μg/ml leupeptin, pepstatin,antipain at 4° C. overnight and then loaded onto a hydroxiapatite column(0.1 g per 1 ml of suspension, equilibrated with 10 mM potassiumphosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column is washed withfour volumes of equilibration buffer at a flow rate of 20 to 30 ml/h.The HSL is eluted with one volume of equilibration buffer containing 0.5M potassium phosphate and then dialyzed (see above) and concentrated 5-to 10-fold by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4° C. Thepartially purified HSL can be stored at −70° C. for 4 to 6 weeks.

1.2 HSL Activity Assay:

To prepare the substrate, 25-50 μCi of [3H]trioleoylglycerol (intoluene), 6.8 μmol of unlabeled trioleoylglycerol and 0.6 mg ofphospholipids (phosphatidylcholine/phosphatidylinositol 3:1 w/v) aremixed, dried with N₂ and then taken up in 2 ml of 0.1 M KPi (pH 7.0) byultrasound treatment (Branson 250, microtip, setting 1-2, 2×1 min withan interval of 1 min). After addition of 1 ml of KPi and renewedultrasound treatment (4×30 sec on ice with intervals of 30 sec), 1 ml of20% BSA (in KPi) is added (final concentration of trioleoylglycerol 1.7mM). For the reaction, 100 μl of substrate solution are pipetted into100 μl of HSL solution (HSL prepared as above, diluted in 20 mM KPi, pH7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 μg/ml pepstatin, 10 μg/mlleupeptin) and incubated at 37° C. for 30 min. Addition of 3.25 ml ofmethanol/chloroform/heptane (10:9:7) and of 1.05 ml of 0.1 M K₂CO₃, 0.1M boric acid (pH 10.5) is followed by thorough mixing and finallycentrifugation (800×g, 20 min). After phase separation, one equivalentof the upper phase (1 ml) is removed and the radioactivity is determinedby liquid scintillation measurement.

1.3 Evaluation of the HSL-Inhibitory Effect:

Substances are normally tested in four independent mixtures. Theinhibition of the HSL enzymatic activity by a test substance isdetermined by comparing with an uninhibited control reaction. The IC₅₀is calculated from an inhibition plot with at least 10 concentrations ofthe test substance. The GRAPHIT, Elsevier-BIOSOFT software package isused to analyze the data.

2. EL Inhibition Assay:

2.1. Preparation of EL

EL is released as secretory protein in high concentration into cellculture medium (conditioned medium) by recombinant cell lines (CHO,HEK293). This is employed as enzyme solution after concentration.

2.2. EL Activity Assay

The phospholipase-specific substrate1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecanoyl)-sn-glycero-3-phosphocholine,(manufacturer Molecular Probes) is used to characterize the enzymaticactivity of endothelial lipase and the effect of inhibitors. Hydrolysisof the A1 ester linkage of this phospholipid by the enzyme liberates thefluorescent dye Bodipy which can be detected after separation bythin-layer chromatography on an HPTLC plate (silica gel 60, Merck) ordirectly in the reaction vessel by measuring the fluorescence.

The substrate solution is prepared by taking up 100 μg of1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecanoyl)-sn-glycero-3-phospho-choline(manufacturer Molecular Probes), 2.4 mg of tripalmitin (Sigma) and 7.9mg of DOP—choline (1,2-dioleoyl-sn-glycero-3-phosphocholine) in 393 μlof chloroform and then transferring 157 μl into a fresh reaction vessel.After evaporation of the solvent, the lipid mixture is dissolved in 4 mlof 200 mM TRIS-HCl, 150 mM sodium chloride, pH=7.4, by sonication twice.The subsequent enzymic reaction takes place at 37° C. for 60 minutes.For this purpose, 45 μl of the substrate solution are incubated with 1μl of inhibitor of appropriate concentration (dissolved in DMSO, pureDMSO solution is used as control) and 5 μl of enzyme solution(conditioned medium). Then 3 μl of the assay mixture are loaded onto anHPTLC plate (silica gel 60, Merck), and the liberated fluorescent dye isseparated for detection with an eluent (diethyl ether:petroleumbenzine:acetic acid [78:22:1]). After evaporation of the eluent, theplate is read in a fluorescence scanner. An increased liberation of thefluorescent dye in the uninhibited reaction is to be observed as ameasure of the enzymic activity.

2.3. Evaluation of the EL-Inhibitory Effect:

The enzymatic activity is reduced as a function of the inhibitorconcentration used, and the inhibitor concentration at which ahalf-maximum enzymatic activity is observed is called IC₅₀.

2.4. Further EL Inhibition Assay:

The phospholipase-specific substrate1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecanoyl)-sn-glycero-3-phosphocholine,(manufacturer Molecular Probes) is used to characterize the enzymaticactivity of endothelial lipase and the effect of inhibitors. Hydrolysisof the A1 ester linkage of this phospholipid by the enzyme liberates thefluorescent dye Bodipy which can be detected after separation bythin-layer chromatography on an HPTLC plate (silica gel 60, Merck) ordirectly in the reaction vessel by measuring the fluorescence.

The substrate solution is prepared by dissolving 100 pg of1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecanoyl)-sn-glycero-3-phospho-choline(manufacturer Molecular Probes) in 100 μl of DMSO and taking up in 2.4mg of tripalmitin (Sigma) in 393 μl of chloroform which comprises 20mg/ml DOP—choline (1,2-dioleoyl-sn-glycero-3-phosphocholine). 39.3 μl ofthis lipid mixture are transferred into a fresh reaction vessel, and thesolvent is evaporated off. The lipid mixture is dissolved in 4 ml of 200mM TRIS-HCl, 150 mM sodium chloride, pH=7.4, by sonication twice. Thesubsequent enzymic reaction takes place at 37° C. for 90 minutes. Forthis purpose, 20 μl of the substrate solution are incubated with 2 μl ofinhibitor of appropriate concentration (dissolved in 10% DMSO, using 10%strength DMSO solution for control) and 2 μl of enzyme solution(conditioned medium). The 4 μl of the assay mixture are loaded onto anHPTLC plate (silica gel 60, Merck), and the liberated fluorescent dye isseparated for detection with an eluent (diethyl ether:petroleumbenzine:acetic acid [78:22:1]). After evaporation of the eluent, theplate is read in a fluorescence scanner. An increased liberation of thefluorescent dye in the uninhibited reaction is to be observed as ameasure of the enzymic activity.

In this assay, the compounds of the examples showed the following IC₅₀values:

IC₅₀ Example [μM] EL 1 0.05 2 0.01 3 0.069 4 0.39 5 0.01 9 0.011 110.354 13 0.0005 14 0.18 15 0.23 16 0.18 17 0.061 18 0.48 19 0.083 200.09

Preparation Processes

The compounds of the invention of the general formula I are prepared bymethods known per se, e.g. by acylation of substituted or unsubstitutedazolopyridin-2-one derivatives II with carbamoyl chlorides III (methodA), or in two stages by reacting azolopyridin-2-one derivatives II withphosgene or equivalents such as trichloromethyl chlorocarbonate,ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and furtherreaction of the resulting azolopyridin-2-onecarboxylic acid derivativewith amines IV (method B). For compounds in which R2 is hydrogen, theazolopyridin-2-one derivatives II can also be reacted with theappropriate isocyanates V R1-N═C═O.

Since acids are usually liberated in these reactions, it is advisable toadd bases such as pyridine, triethylamine, sodium hydroxide solution oralkali metal carbonates for expedition. The reactions can be carried outin wide temperature ranges. It has usually proved to be advantageous tooperate at from 0° C. to the boiling point of the solvent used. Examplesof solvents employed are methylene chloride, THF, DMF, toluene, ethylacetate, n-heptane, dioxane, diethyl ether or pyridine. If anhydrousconditions are used, strong bases such as lithium hydride, sodiumhydride or potassium tert-butoxide in aprotic solvents such as THF orDMF have also proved suitable.

The azolopyridin-2-one derivatives or corresponding aza-substitutedderivatives employed as starting compounds II are commercially availableor can be prepared by processes known from the literature (e.g. C.Flouzat, Y. Bresson, A. Mattio, J. Bonnet, G. Guillaumet J. Med. Chem.1993, 36, 497-503; F. Mutterer, C. D. Weis, J. Het. Chem. 1976, 13,1103-1104; K. Bowden, G. Crank, W. J. Ross, J. Chem. Soc. 1968,172-185).

The examples detailed below serve to illustrate the invention without,however, restricting it.

EXAMPLES Example 12-Oxo-oxazolo[4,5-b]pyridin-3-(2-methylbenzyl)carboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were dissolved in5 ml of THF. Addition of 129.8 mg (0.882 mmol) of 2-methylbenzylisocyanate was followed by stirring at 70° C. for 5 h, addition onceagain of the same amount of 2-methylbenzyl isocyanate, and stirring 70°C. for 5 h. The reaction mixture was concentrated and purified bypreparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 55 mg(26%), M+H+: 284.1.

Example 26-Bromo-2-oxo-oxazolo[4,5-b]pyridine-3-(2-methylbenzyl)carboxamide

100 mg (0.465 mmol) of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one werereacted in analogy to Example 1 with 102.7 mg (0.698 mmol) of2-methylbenzyl isocyanate in THF at 70° C. Yield: 13 mg (8%), M+H+:362.05.

Example 3 2-Oxo-oxazolo[4,5-b]pyridine-3-hexylcarboxamide

100 mg (0.74 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 102.8 mg (0.809 mmol) of 1-isocyanatohexane indioxane at 80° C. Yield: 77 mg (40%), M+H+: 264.12.

Example 4 2-Oxo-oxazolo[4,5-b]pyridine-3-(3-methylbenzyl)carboxamide

200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 324.3 mg (2.2 mmol) of1-isocyanatomethyl-3-methylbenzene in dioxane at 80° C. Yield: 322 mg(77%), M+H+: 284.1.

Example 5 2-Oxo-oxazolo[4,5-b]pyridine-3-(3,4-dimethylbenzyl)carboxamide

200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 284 mg (1.76 mmol) of 3,4-dimethylbenzylisocyanate in dioxane at 80° C. Yield: 110 mg (25%), M+H+: 298.1.

Example 63-(4-Methylpiperidine-1-carbonyl)-3H-oxazolo[4,5-b]pyridin-2-one

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one, 235 mg (1.45mmol) of 4-methylpiperidine-1-carbonyl chloride and 101 μl (2.18 mmol)of triethylamine were stirred in 5 ml of pyridine at room temperaturefor 3 h. The reaction mixture was concentrated, and the residue wasdissolved in water and extracted with ethyl acetate. The organic phasewas concentrated and purified by preparative HPLC (PR18,acetonitrile/water 0.1% TFA). Yield: 6 mg (3%), M+H+: 262.12.

Example 76-Bromo-3-(4-methylpiperidine-1-carbonyl)-3H-oxazolo[4,5-b]pyridin-2-one

100 mg (0.46 mmol) of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one werereacted in analogy to Example 6 with 150 mg (0.93 mmol) of4-methylpiperidin-1-carbonyl chloride. Yield: 78 mg (50%), M+H+: 340.09.

Example 8 2-Oxo-oxazolo[4,5-b]pyridine-3-phenethylcarboxamide

300 mg (2.2 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 389 mg (2.6 mmol) of(2-isocyanatoethyl)benzene in dioxane at 80° C. Yield: 436 mg (70%),M+H+: 284.07.

Example 9 2-Oxo-oxazolo[4,5-b]pyridine-3-heptylcarboxamide

200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 207 mg (1.47 mmol) of 1-isocyanatoheptane indioxane at 80° C. Yield: 416 mg (10%), M+H+: 278.15.

Example 10 2-Oxo-oxazolo[4,5-b]pyridine-3-benzylcarboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 117 mg (0.88 mmol) of isocyanatomethylbenzenein dioxane at 80° C. Yield: 30 mg (15%), M+H+: 270.11.

Example 11 2-Oxo-oxazolo[4,5-b]pyridine-3-butylcarboxamide

300 mg (2.2 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 262 mg (2.6 mmol) of 1-isocyanatobutane indioxane at 80° C. Yield: 91 mg (18%), M+H+: 236.15.

Example 12 6-Bromo-2-oxo-oxazolo[4,5-b]pyridine-3-benzylcarboxamide

100 mg (0.46 mmol) of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one werereacted in analogy to Example 1 with 74.3 mg (0.56 mmol) ofisocyanatomethylbenzene in dioxane at 80° C. Yield: 10 mg (6%), M+H+:348.10.

Example 132-oxo-oxazolo[4,5-b]pyridin-3-(1,2,3,4-tetrahydronaphthalen-1-yl)carboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 127 mg (0.735 mmol) of1-isocyanato-1,2,3,4-tetrahydronaphthalene in dioxane at 80° C. Yield:29 mg (13%), M+H+: 310.10.

Example 14 2-Oxo-oxazolo[4,5-b]pyridine-3-(R)-indan-1-yl)carboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 140 mg (0.88 mmol) of (R)-1-isocyanatoindanein dioxane at 60° C. Yield: 22 mg (10%), M+H+: 296.14.

Example 15 2-Oxo-oxazolo[4,5-b]pyridine-3-(S)-indan-1-yl)carboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 140 mg (0.88 mmol) of (S)-1-isocyanatoindanein dioxane at 60° C. Yield: 8 mg (40%), M+H+: 296.14.

Example 16 2-Oxo-oxazolo[4,5-b]pyridin-3-dodecylcarboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 155.3 mg (0.735 mmol) of 1-isocyanatododecanein dioxane at 80° C. Yield: 33 mg (13%), M+H+: 348.25.

Example 175-Methyl-2-oxo-oxazolo[4,5-b]pyridine-3-(2-methylbenzyl)carboxamide

150 mg (1 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one were reactedin analogy to Example 1 with 176 mg (1.2 mmol) of1-isocyanatomethyl-2-methylbenzene and 100 μl of pyridine in toluene at115° C. Yield: 3 mg (1%), M+H+: 298.13.

Example 18 2-Oxo-oxazolo[4,5-b]pyridine-3-cyclohexylmethylcarboxamide

100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 102 mg (0.735 mmol) ofisocyanatomethylcyclohexane in dioxane at 80° C. Yield: 43 mg (21%),M+H+: 276.13.

Example 19 2-Oxo-oxazolo[4,5-b]pyridine-3-octylcarboxamide

200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 273.7 mg (1.76 mmol) of 1-isocyanatooctane indioxane at 80° C. Yield: 40 mg (9%), M+H+: 292.10.

Example 20 2-Oxo-oxazolo[4,5-b]pyridine-3-nonylcarboxamide

200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted inanalogy to Example 1 with 298.4 mg (1.76 mmol) of 1-isocyanatononane indioxane at 80° C. Yield: 40 mg (9%), M+H+: 306.20.

1-15. (canceled)
 16. A method for the treatment or prevention of insulinresistance in a patient, which comprises administering to said patient atherapeutically effective amount of a compound of formula I

wherein: is independently selected from ═C(—R)— and ═N—, with theproviso that at least one and at most two of X is ═N—; Y is —O— or —S—;R is independently selected from hydrogen, halogen, (C₁-C₆)-alkyl,(C₁-C₃alkyloxy-(C₁-C₃)-alkylene, hydroxy, (C₁-C₆)-alkylmercapto, amino,(C₁-C₆E alkylamino, di-(C₇-C₁₂)-alkylamino, (C₁-C₆)-alkylcarbonyl,COOR3, trifluoromethyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl,pentafluorosulfanyl, (C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl, CO—NR6R7,O—CO—NR6R7, O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl,O—CO—(C₁-C₆)-alkylene-CO—OH, O—CO—(C₁-C₆)-alkylene-CO—NR6R7 andunsubstituted or mono- or poly-F-substituted (C₁-C₆)-alkyloxy; R1 isselected from (C₄-C₁₆)-alkyl, (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl, (C₁-C₄)alkylene-(C₅-C₁₂)-heteroaryl, (C₁-C₄)-alkylene-(C₃-C₁₂)-cycloalkyl, and(C₈-C₁₄)-bicycle, wherein each of said aryl, heteroaryl, cycloalkyl andbicycle may be substituted one or more times by a substituent selectedfrom halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy, hydroxy,(C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-(C₂-C₁₂)-alkylamino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₈)-alklaminocarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy,(C₁-C₆)-alkylsulfonyl, and aminosulfonyl; R2 is selected from hydrogenand (C₁-C₆)-alkyl; or, in the alternative, R1 and R2 form, together withthe nitrogen atom to which they are attached, a monocyclic, saturated orpartially unsaturated 4- to 7-membered ring system or a bicyclicsaturated or partially unsaturated 8- to 14-membered ring system, ofwhich individual members of the ring systems may be replaced by one tothree atoms or atomic groups selected from —CHR4-, —CR4R5-, —(C═R4)-,—C(═O)—, —O—, —S—, —SO—, —SO₂—, with the proviso that no two of theunits —O—, —S—, —SO—, and —SO₂— may be adjacent to each other; R3 ishydrogen, (C₁-C₆)-alkyl, or benzyl; R4 and R5 are independently selectedfrom (C₁-C₆)-alkyl, halogen, trifluoromethyl, COOR3, cyclopropyl, andcyclopropylene; and R6 and R7 are independently selected from hydrogen,(C₁-C₆)-alkyl, —(C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl, (C₃-C₁₂)-cycloalkyl,(C₁-C₄)-alkylene-(C₆-C₁₀)-aryl, (C₁-C₄)-alkylene-(C₅-C₁₂)-heteroaryl,(C₁-C₄)-alkylene-(C₄-C₁₂)-cycloalkyl, and (C₈-C₁₄)-bicycle; or apharmaceutically acceptable salt thereof.
 17. A method for the treatmentor prevention of diabetes mellitus and the sequelae associated therewithin a patient, which comprises administering to said patient atherapeutically effective amount of a compound of formula I as claimedin claim 16 or a pharmaceutically acceptable salt thereof.
 18. A methodfor the treatment or prevention of dyslipidemias and the sequelaethereof in a patient, which comprises administering to said patient atherapeutically effective amount of a compound of formula I as claimedin claim 16 or a pharmaceutically acceptable salt thereof.
 19. A methodfor the treatment or prevention of conditions associated with metabolicsyndrome in a patient, which comprises administering to said patient atherapeutically effective amount of a compound of formula I as claimedin claim 16 or a pharmaceutically acceptable salt thereof.
 20. A methodfor the treatment or prevention of conditions associated with reducedHDL level in a patient, which comprises administering to said patient atherapeutically effective amount of a compound of formula I as claimedin claim 16 or a pharmaceutically acceptable salt thereof.
 21. A methodfor the treatment or prevention of atherosclerotic disorders in apatient, which comprises administering to said patient a therapeuticallyeffective amount of a compound of formula I as claimed in claim 16 or apharmaceutically acceptable salt thereof
 22. A process for preparing acompound of formula I as claimed in claim 16, which comprises: acylatingan azolopyridin-2-one derivative of formula II with a carbamoyl chlorideof formula III; or in two stages, reacting said azolopyridin-2-onederivative of formula II first with phosgene or a phosgene equivalentchosen from trichloromethyl chlorocarbonate, ditrichloromethyl carbonateor 4-nitrophenyl chloroformate, and, in a second step, reacting theresulting intermediate with an amine of formula IV, in which thesubstituents are as defined in claim
 16.


23. A process for preparing a compound of formula I as claimed in claim16, wherein R2 is hydrogen, which comprises reacting anazolopyridin-2-one derivative of formula II with an isocyanate offormula V: O═C═N—R1.